Posaconazole (CAS Registry Number 171228-49-2; CAS Name: 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol) is a triazole antifungal drug represented by the structure:

Posaconazole is used, for example, to prevent and/or treat invasive fungal infections caused by Candida species, Mucor species, Aspergillus species, Fusarium species, or Coccidioides species in immunocompromised patients and/or in patients where the disease is refractory to other antifungal agents such as amphothericin B, fluconazole, or itraconazole, and/or in patients who do not tolerate these antifungal agents.
One of the important intermediates for the preparation of posaconazole is the compound of formula (IX)
wherein both residues Y1 and Y2 are F. Therefore, there generally is a constant need for advantageous processes for the preparation of this intermediate.
According to the known prior art processes, a common starting material for the preparation of chiral compounds according to formula (IX) is a substituted olefin compound according to the following formula (II)
wherein L is a suitable leaving group such Cl, Br, and sulfonates.
However, said prior art processes provide only comparatively complicated processes for the preparation of these compounds of formula (II), abbreviated in the following by Ar—C(═CH2)—CH2-L, in particular compounds wherein Y1 and Y2 are both F.
WO 94/25452 discloses a process wherein a Ar—C(═CH2)—CH2-L is obtained by reacting the respective allylic alcohol Ar—C(═CH2)—CH2—OH with either a brominating agent or a sulfonylating agent. In order to obtain the allylic alcohol in turn, several procedures are taught in the literature.
One procedure described in WO 94/25452 starts from Ar—C(═O)—CH2-L from which, in a 3-step process, the allylic alcohol is obtained. In the first step, Ar—C(═O)—CH2—Cl is reacted with KOAc (potassium acetate) to obtain Ar—C(═O)—CH2—OAc which is then subjected to a reaction with CH3Ph3PBr (methyltriphenylphosphonium bromide) and NaHMDS (sodium hexamethyldisilazane) in the presence of THF (tetrahydrofuran) to give Ar—C(═CH2)—CH2—OAc. In the third step, Ar—C(═CH2)—CH2—OAc is further reacted with KOH (potassium hydroxide) to finally obtain Ar—C(═CH2)—CH2—OH. Apart from the fact that this procedure makes use of 3 consecutive steps, each of which has to be carried out in a separate reaction vessel, it is noted that in particular as far as the second step is concerned, the reaction product is not easy to be separated from the by-product triphenylphosphine oxide.
Another procedure described in P. Blundell et al., Synlett 1994, pp. 263-265, starts from Ar—Br which, in a first step, is converted into a Grignard reagent which in turn is reacted with (Cl—CH2)2C═O (1,2-dichloro acetone) wherefrom Ar—C(OH)(CH2Cl)2 is obtained which, in a second step, is treated with potassium carbonate to obtain an epoxide. This epoxide, in turn, is then converted, in a third step, to Ar—C(═CH2)—CH2—OH. Apart from the fact that this procedure for manufacturing the allylic alcohol involves 3 steps, each of which has to be carried out in a separate reaction vessel, it is known that the Grignard reagent derived from Ar—Br, i.e. 2,4-difluoro bromobenzene, is a potentially hazardous compound.
WO 95/16658 A1 suggests another procedure for the preparation of Ar—C(═CH2)—CH2-L which starts from Ar—C(═O)—CH3. In a Grignard reaction with consecutive elimination, the olefin compound Ar—C(═CH2)—CH3 is obtained which is then subjected to radical halogenation to obtain Ar—C(═CH2)—CH2-L (with L=Cl, Br). Compared to the two procedures discussed above, this procedure provides a process which, although involving 3 steps, can be carried out in only 2 reaction vessels, due to the fact that the Grignard reaction and the subsequent elimination are carried out in a single vessel. A major drawback of this procedure, however, has to be seen in the fact that the radical halogenation gives an undesired mixture of allyl halides and vinyl halides.
Therefore, it was an object of the present invention to provide an improved process for the preparation of a chiral compound of formula (IX) wherein the starting material, the compound of formula (II), is prepared by a novel process which is advantageous over said known prior art processes.
It was found that said starting material can be prepared by a process which can be carried out in only one single reaction vessel with good yields, wherein the process consists of only 2 reaction steps. Surprisingly, an olefination concept known as Peterson olefination could be applied for the preparation of above-mentioned allylic chloride. According to this olefination which is first described in “D. J. Peterson, Carbonyl olefination reaction using silyl-substituted organometallic compounds; J. Org. Chem. (1968) 33 (2) pp. 780-784”, an alpha-silyl carbanion is reacted with ketones or aldehydes to form beta-hydroxysilanes which may eliminate to form alkenes. The vast majority of known examples using Peterson olefination are carried in diethyl ether which cannot be used in industrial scale processes due to safety aspects. In rare cases, tetrahydrofuran is described as an alternative solvent.
As discussed above, the compounds of formula (IX) and salts thereof are important intermediates for the preparation of antifungal agents. Due to several reasons, the presence of such intermediates as crystalline compounds is advantageous. However, from the known processes of the literature, compounds of formula (IX) and salts thereof, in particular compounds of formula (IX) with both Y1 and Y2 being F, are not obtained as at least partially crystalline compounds.
Therefore, it was another object of the present invention to provide a process from which the compound according to formula (IX) and salts thereof, in particular compounds of formula (IX) with both Y1 and Y2 being F, are obtained as at least partially crystalline compound.
It was yet another object of the present invention to provide the compound according to to formula (IX) and salts thereof, in particular compounds of formula (IX) with both Y1 and Y2 being F, as at least partially crystalline compound.